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Background: People have long been fascinated with the size and growth of living things, from the giants of classic mythology and art to the little people who also have appeared in classical art, as well as the courts of European monarchs, and were exploited in "shows." Serious medical evaluation began in the late 19th century with the description of acromegaly and its association with pituitary tumors. In the early 20th century, multiple investigators attempted to extract a growth-promoting factor from the anterior pituitary and then, over the decades, to purify it and distinguish it from other anterior pituitary hormones. With relatively pure growth hormone (GH), its biological activity in growth promotion and as a metabolic hormone were studied, and species specificity became apparent: primate GH was the only GH active in man. Human GH was prepared from cadaveric pituitaries and distributed by the NIH to treat children with GH deficiency, but there was never enough pituitary hGH for all of the children who required it. When Creutzfeldt-Jakob disease was found in some patients who received pituitary GH, the production and FDA approval of biosynthetic hGH dramatically accelerated. With a large supply, one could treat those who were GH deficient and test its efficacy in other causes of short stature; longer acting versions of hGH have now been developed, tested, and in a few instances received FDA approval., Summary: It has been a long journey from the description of over- and underproduction of GH in animals to the production and clinical use of the biosynthetic hormones., Key Messages: The efforts of basic scientists led to the extraction and purification of GH. Clinical scientists have expanded the appropriate use of hGH for short children with conditions in addition to GH deficiency., (© 2022 S. Karger AG, Basel.)

Objective: The skeletal remains of a short-statured individual (T17) are described and a differential diagnosis performed to determine the etiology of the condition., Materials: An individual considered pathologically short in stature was discovered in the burial site of Piazza XX Settembre, Modena (northern Italy)., Methods: Morphological and morphometric analyses were performed, and T17 was compared to dwarfs from other localities and periods and to the adult female population from the same site. A paleopathological survey was undertaken to assess the degree of the skeletal elements of T17 were affected., Results: T17 was a female, 20-30 years of age at death, with a stature of 128 cm and disproportionate dwarfism associated with congenital skeletal dysplasia., Conclusions: T17 likely affected by a form of hypochondroplasia., Significance: Anatomical consequences of hypochondroplasia are presented, and the timeframe and associated burial goods suggest a 6th-century Lombard short stature belonging to one of the earliest Lombard settlements in Italy., Suggestions for Further Research: Future genetic analysis would resolve if the mutation in the type 3 fibroblast growth factor receptor (FGFR3) is present in the remains of T17; however, it is not exclusivly linked to hypochondroplasia., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A 66 year-old woman with a disproportionate dwarfism and who bore seven children was discovered at the Middenbeemster archaeological site (The Netherlands). Three are perinates and show no macroscopic or radiological evidence for a FGFR3 mutation causing hypo-or achondroplasia. This mutation induces dysfunction of the growth cartilage, leading to abnormalities in the development of trabecular bone. Because the mutation is autosomal dominant, these perinates have a 50% risk of having been affected. This study determines whether trabecular bone microarchitecture (TBMA) analysis is useful for detecting genetic dwarfism. Proximal metaphyses of humeri were μCT-scanned with a resolution of 7-12 μm. Three volumes of interest were segmented from each bone with TIVMI© software. The TBMA was quantified in BoneJ© using six parameters on which a multivariate analysis was then performed. Two of the Middenbeemster perinates show a quantitatively different TBMA organization. These results and the family's medical history suggest a diagnosis of genetic dwarfism for this two perinates. This study provides evidence to support the efficacy of μCT for diagnosing early-stage bone disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

"Healing is best accomplished when art and science are conjoined, when body and spirit are probed together", says Bernard Lown, in his book "The Lost Art of Healing". Art has long been a witness to disease either through diseases which affected artists or diseases afflicting objects of their art. In particular, artists have often portrayed genetic disorders and malformations in their work. Sometimes genetic disorders have mystical significance; other times simply have intrinsic interest. Recognizing genetic disorders is also an art form. From the very beginning of my work as a Medical Geneticist I have composed personal "algorithms" to piece together evidence of genetics syndromes and diseases from the observable signs and symptoms. In this paper we apply some 'gestalt' Genetic Syndrome Diagnostic algorithms to virtual patients found in some art masterpieces. In some the diagnosis is clear and in others the artists' depiction only supports a speculative differential diagnosis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Agnolo Bronzino's painting of Nano Morgante depicts for the first time the anatomy of a dwarf. This image testifies Cosimo's special interest for this dwarf. In Antonio Francesco Grazzini's poem written in Nano Morgante's honor, we underline some interesting aspects of his physical deformities and his small height, which are highly praised as we can see them on the painting.

Allegedly kidnapped from a secret city in Central America, the "Aztec children" began a showman's career in the early-1850s. They died around 1900, after being observed by countless pathologists and ethnologists from Europe and the US. Most of the literature on the "Aztec children" has emphasized racial theories, the imperial gaze, and the character of "ethnological shows", where monstrosity and ethnicity were practically synonymous. Less attention has been paid to the fact that scientists continuously insisted that the case was false, an argument that instead of debunking the myth of the "Aztec children", contributed to establishing the "Aztecs" as "a matter of fact". In examining the case of the "Aztec children", this essay aims to explore what can be called the shifting nature or elusiveness of falsehood.

Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) II has recently been defined as a PCNT gene defect. Historically, it has been a disorder of interest because of the severe intrauterine growth restriction and postnatal short stature. The very shortest/smallest mature human being undoubtedly had this disorder. Maria Zarate lived between 1864 and 1890 and traveled in sideshows to England and all over North America. Her exceeding short stature was well documented in photographs and by a group of physicians in England. She was Mexican and also had an affected brother. A museum, Museo Casa Grande, about her still exists in Cempoala, Mexico., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This review critically examines the findings which characterize the dysmorphic, radiologic and behavioral phenotype of Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) and has an historical perspective on it. MOPD is a group of primordial dwarfism syndromes with prenatal onset growth retardation, a typical craniofacial appearance and behavioral phenotype. In 1959, Mann and Russell have described the first case in a detailed report, and named "microcephalic midget of extreme type". In their report; based on historical records and a small painting, they pointed "Mademoiselle Crachami" as the oldest known case.

Since antique times, dwarfs have been commonly employed at court, mostly as servants, entertainers, or personal attendants upon noble women and noblemen. Their presence at European Renaissance courts was very common, as demonstrated by their presence alongside to their masters or mistress in several artworks of that period. Aim of our paper is to derive clinical information regarding the type of dwarfism affecting people living and acting at European courts from an overview of paintings dating fifteenth to the eighteenth century.

The ancient Egyptian civilization lasted for over 3000 years and ended in 30 BCE. Many aspects of ancient Egyptian culture, including the existence of skeletal dysplasias, and in particular achondroplasia, are well known through the monuments and records that survived until modern times. The hot and dry climate in Egypt allowed for the preservation of bodies and skeletal anomalies. The oldest dwarf skeleton, the Badarian skeleton (4500 BCE), possibly represents an epiphyseal disorder. Among the remains of dwarfs with achondroplasia from ancient Egypt (2686-2190 BCE), exists a skeleton of a pregnant female, believed to have died during delivery with a baby's remains in situ. British museums have partial skeletons of dwarfs with achondroplasia, humeri probably affected with mucopolysaccharidoses, and a skeleton of a child with osteogenesis imperfecta. Skeletal dysplasia is also found among royal remains. The mummy of the pharaoh Siptah (1342-1197 BCE) shows a deformity of the left leg and foot. A mummified fetus, believed to be the daughter of king Tutankhamun, has scoliosis, spina bifida, and Sprengel deformity. In 2006 I reviewed the previously existing knowledge of dwarfism in ancient Egypt. The purpose of this second historical review is to add to that knowledge with an expanded contribution. The artistic documentation of people with skeletal dysplasia from ancient Egypt is plentiful including hundreds of amulets, statues, and drawing on tomb and temple walls. Examination of artistic reliefs provides a glance of the role of people with skeletal dysplasia and the societal attitudes toward them. Both artistic evidence and moral teachings in ancient Egypt reveal wide integration of individuals with disabilities into the society., (Copyright (c) 2008 Wiley-Liss, Inc.)

Fossils from Liang Bua (LB) on Flores, Indonesia, including a nearly complete skeleton (LB1) dated to 18kyr BP, were assigned to a new species, Homo floresiensis. We hypothesize that these individuals are myxoedematous endemic (ME) cretins, part of an inland population of (mostly unaffected) Homo sapiens. ME cretins are born without a functioning thyroid; their congenital hypothyroidism leads to severe dwarfism and reduced brain size, but less severe mental retardation and motor disability than neurological endemic cretins. We show that the fossils display many signs of congenital hypothyroidism, including enlarged pituitary fossa, and that distinctive primitive features of LB1 such as the double rooted lower premolar and the primitive wrist morphology are consistent with the hypothesis. We find that the null hypothesis (that LB1 is not a cretin) is rejected by the pituitary fossa size of LB1, and by multivariate analyses of cranial measures. We show that critical environmental factors were potentially present on Flores, how remains of cretins but not of unaffected individuals could be preserved in caves, and that extant oral traditions may provide a record of cretinism.

Ancient Egypt was one of the most advanced and productive civilizations in antiquity, spanning 3000 years before the "Christian" era. Ancient Egyptians built colossal temples and magnificent tombs to honor their gods and religious leaders. Their hieroglyphic language, system of organization, and recording of events give contemporary researchers insights into their daily activities. Based on the record left by their art, the ancient Egyptians documented the presence of dwarfs in almost every facet of life. Due to the hot dry climate and natural and artificial mummification, Egypt is a major source of information on achondroplasia in the old world. The remains of dwarfs are abundant and include complete and partial skeletons. Dwarfs were employed as personal attendants, animal tenders, jewelers, and entertainers. Several high-ranking dwarfs especially from the Old Kingdom (2700-2190 BCE) achieved important status and had lavish burial places close to the pyramids. Their costly tombs in the royal cemeteries and the inscriptions on their statutes indicate their high-ranking position in Egyptian society and their close relation to the king. Some of them were Seneb, Pereniankh, Khnumhotpe, and Djeder. There were at least two dwarf gods, Ptah and Bes. The god Ptah was associated with regeneration and rejuvenation. The god Bes was a protector of sexuality, childbirth, women, and children. He was a favored deity particularly during the Greco-Roman period. His temple was recently excavated in the Baharia oasis in the middle of Egypt. The burial sites and artistic sources provide glimpses of the positions of dwarfs in daily life in ancient Egypt. Dwarfs were accepted in ancient Egypt; their recorded daily activities suggest assimilation into daily life, and their disorder was not shown as a physical handicap. Wisdom writings and moral teachings in ancient Egypt commanded respect for dwarfs and other individuals with disabilities., (Copyright (c) 2005 Wiley-Liss, Inc.)

The evolution of the status of dwarfs in the Hellenistic and Roman period is witnessed by a number of evidence, mainly iconographic. This paper revisits extant representations at the light of ancient medical texts and physiognomics. Most objects relate short-statured people with the world of entertainement (musicians, athletes) and reveal their continuing function as good-luck bringers.

Clinical and laboratory investigations starting in 1958 of a group of dwarfed children resembling isolated GH deficiency but who had very high serum levels of GH led to the description of the syndrome of primary GH resistance or insensitivity (Laron syndrome) and subsequently to the discovery of its molecular defects residing in the GH receptor and leading to an inability of IGF-I generation. With the biosynthesis of IGF-I in 1986, therapeutic trials started. Continuously more and more patients are being diagnosed in many parts of the world with a variety of molecular defects. This syndrome proved to be a unique model that enables the study of the consequences of GH receptor defects, the physiopathology of GH-IGF-I disruption, and comparison of the GH-independent IGF-I effects. This review presents the personal experience gained from the study follow-up and treatment of the 60 patients followed up for many years in the Israeli cohort.

The purpose of this paper is to explore the visual representation of dignity, through the particular example of the seventeenth century Spanish painter Diego Velázquez. Velázquez works at a point in Western history when modern conceptions of dignity are beginning to be formed. It is argued that Velázquez' portraits of royalty and aristocracy articulate a tension between a feudal conception of majesty and a modern conception of the dignity of merit. On this level, modern conceptions of dignity of merit are understood in terms of a struggle to excel in particular activities, and thus to overcome the risk of failure. More radically, Velázquez' portraits of dwarfs and the mentally disabled are argued to be expressive of dignity, not by finding a positive representation of the sitter's dignity, or to find scales of activities by which they can be positively assessed, but rather by grounding their dignity, negatively, in a protest against indignity and humiliation. Drawing on Honneth's analysis of dignity in terms of a theory of recognition, it is argued that the indignity of the court dwarf lies in the fracturing of their communication with the rest of society. The task of repairing that fractured communication is achieved, not by representing a dignified ideal, but rather by drawing attention to the prejudices that serve to exclude the humiliated from full participation in society. In conclusion, it is suggested that the conceptualisation and representation of the elderly today finds effective exemplars in Velázquez' portraits of court dwarfs, rather than in his portraits of the elderly.

The skeleton of Caroline Crachami is a rare historical example of primordial microcephalic dwarfism (PMD). Studies show the condition to be heterogeneous, with at least three types, for which the assessment criteria rely on descriptive evaluations and/or simple measures with regard to cranial features. Advances in noninvasive imaging allow for a more complete morphometric examination of the skull of Caroline Crachami with the aim of clarifying aspects of the condition. In the present study, the skull of Caroline Crachami was three-dimensionally imaged with computed tomography (CT) and reconstructed in virtual space. Coordinates for a number of measurements were taken to represent interesting anatomies with an emphasis on those measures not easily replicated on the skull itself. Volumes of the endocranial cavity and sella turcica were also computed. These data were compared with normative values taken from the literature and measured from CT images of the Bosma collection. Findings indicate that the general size of the skull is equivalent to that of a 6- to 8-month-old, that the endocranial volume and cranial base angle are commensurate with that of a newborn, and that the sella volume is the same as that for an 8- to 15-month-old. Apart from these traits, the skull was well proportioned and within the range of normal variation for a skull aged between 2-9 years. We conclude that further quantitative analysis on related skulls is warranted in the study of PMD using the methods and techniques described., (Copyright 2002 Wiley-Liss, Inc.)

The question of why Hephaestus, the Greek god of smiths, limped has been the subject of much debate, mainly on mythological grounds. This debate extended also into the field of medical diagnosis, with attempts at defining the nature of the deformity that made the crippled Hephaestus the buffoon of the other Olympic gods. One problem encountered in these debates was the changes to which the ugly young Hephaestus was subjected with the passing of time-from a limping deformed youth to the later dignified and normal man. While some authors, largely influenced by poetic Greek texts and vase paintings, attributed the limp to talipes (club-feet), others pointed to certain features suggestive of achondroplasia. Since the image of the early Hephaestus is based mainly on the much earlier concept of the Egyptian god Ptah, who as the triune god of the resurrection sometimes is depicted as an achondroplastic dwarf (Ptah-Pataikos), the suggestion of the possible achondroplastic dwarf-like nature of the early Hephaestus is not implausible. It is supported by similarities in the image of Hephaestus to some features in other Egyptian gods, such as the domestic god Bes, the guardian of the new-born, and the Horus the Child or Harpocrates (Greek), yet another protector of youth and "the symbol of everything that is young and vigorous" [Budge, 1969: The Gods of the Egyptians, or Studies in Egyptian Mythology. Volume I.]. The characteristic feature of this child-god is the "lock of Harpocrates" on the right side of his head. That this lock can sometimes also be seen not only on the head of Ptah-Pataikos and of Bes but also on the young Hephaestus is highly suggestive of the Egyptian influence on his image. Recently, however, another interesting explanation of Hephaestus's limp has been suggested that may explain why the Egyptian influenced image of the early achondroplastic Hephaestus changed to the later, more Grecian view of the smith-god who hobbled because of club-feet. Improvements in composition-analysis of samples from antique statues and various utensils have led to the suggestion that the introduction of new smelting techniques in antique times may have exposed ancient metal workers to the effects of various toxic metals causing, for instance, chronic lead poisoning or, more relevant here, chronic arsenic poisoning causing peripheral neuritis with weakness and lameness of one or both lower extremities. Later changes in smelting technique, and recognition or guess-work of a possible connection between these techniques and toxic effects, may explain the change from the buffoon-like achondroplastic walk to the club-footed limp and eventual normal behaviour of Hephaestus, the Smith. In other words: Did Hephaestus limp because of his arsen-neuritis?

A collection of 893 historical picture postcards from 1900 to 1935, depicting dwarfs and giants, was analysed from medical and psychosocial viewpoints. In conditions such as 'bird headed dwarfism', achondroplasia, cretinism, so-called Aztecs or pinheads, Grebe chondrodysplasia, and acromegalic gigantism, the disorder could be diagnosed easily. In hypopituitary dwarfism, exact diagnosis was more difficult because of heterogeneity. The most common conditions depicted were pituitary dwarfism and achondroplasia. Most of those with gigantism had pituitary gigantism and acromegaly. Brothers and sisters or parents and their children provided evidence of mendelian inheritance of some of these disorders. The cards suggest that being put on show provided, at least in some cases, social benefits.

Caroline Crachami (C.C.) considered to have had the Seckel syndrome was one of the most extreme cases of dwarfism ever recorded. Reputedly born in Sicily in 1815, she attracted much attention when exhibited in England before her death on 3 June 1824. Although she is said to have been 9 years old at death, published descriptions give her a dental age varying from 2 to 7 years. Examination of her skull in the Royal College of Surgeons of England demonstrated a more or less erupted complete deciduous dentition, with no erupted permanent teeth. Radiographs showed agenesis of several permanent teeth. It was concluded that the dental age of C.C. was 3 years (+/- 6 months). Perikymata were evident in the surface enamel encircling the crown of the partially exposed maxillary left first permanent molar. Their distribution and spacing were normal, with no evidence of developmental retardation. The distance between the periradicular bands in the root near the cement-enamel junction was also normal. We conclude that the dental age of C.C. was similar to her chronological age and that at death she was about 3 and not 9 years old. The reason that she was said to be nearly 9 when exhibited in England we believe was related to financial considerations, as people would be generally less impressed with a dwarf only 3 years old. The new age we give C.C. has implications on the diagnosis of her medical condition.

Several malformed individuals were presented at the World Exhibition in Antwerp in 1894. Among them was Mrs. Alice Vance from Mount Pleasant, Texas, with congenital limb defects, and Mr. Eugen Berry, who had asymmetrical, monstrous enlargement and macrodactyly of the feet, i.e., Proteus syndrome. After the World Exhibition Mrs. Vance presented herself to the public in Castan's Panopticon imitating a bear. She became famous under the stage name "Das Bärenweib" ("the bear-like woman") and was examined by several German clinicians, and her malformations were considered to be of high scientific interest. Mrs. Vance had mesomelic dwarfism and her mother was known to have similar malformations. Her limb deficiencies were generally considered a unique congenital condition those days, and the diagnosis of "a maternally inherited malformation of the forearms and the shanks" [Daffner 1898: Munch Med Wochenschr 25:782] was made. Virchow [1897: Verh Berl Ges Ethnol Urgeschichte 29:624], feeling attacked by a daily newspaper stating that the physicians as well as the police of Berlin had missed the diagnosis of an "English disease," eventually exercised his authority and diagnosed Alice Vance as a "phocomelic." Clearly, she was not a phocomelic according to past and current definition of this term. Thus, from a historical point of view, the story illustrates how pressure from the daily press altered the definition of an up-to-then precisely defined medical term for decades. According to the clinical data and an X-ray report available from the literature, Alice Vance had a dominantly inherited type of mesomelic dwarfism. We propose the diagnosis of Nievergelt syndrome.